2,001 research outputs found
Pathway-Based Genomics Prediction using Generalized Elastic Net.
We present a novel regularization scheme called The Generalized Elastic Net (GELnet) that incorporates gene pathway information into feature selection. The proposed formulation is applicable to a wide variety of problems in which the interpretation of predictive features using known molecular interactions is desired. The method naturally steers solutions toward sets of mechanistically interlinked genes. Using experiments on synthetic data, we demonstrate that pathway-guided results maintain, and often improve, the accuracy of predictors even in cases where the full gene network is unknown. We apply the method to predict the drug response of breast cancer cell lines. GELnet is able to reveal genetic determinants of sensitivity and resistance for several compounds. In particular, for an EGFR/HER2 inhibitor, it finds a possible trans-differentiation resistance mechanism missed by the corresponding pathway agnostic approach
Structured penalized regression for drug sensitivity prediction
Large-scale {\it in vitro} drug sensitivity screens are an important tool in
personalized oncology to predict the effectiveness of potential cancer drugs.
The prediction of the sensitivity of cancer cell lines to a panel of drugs is a
multivariate regression problem with high-dimensional heterogeneous multi-omics
data as input data and with potentially strong correlations between the outcome
variables which represent the sensitivity to the different drugs. We propose a
joint penalized regression approach with structured penalty terms which allow
us to utilize the correlation structure between drugs with group-lasso-type
penalties and at the same time address the heterogeneity between omics data
sources by introducing data-source-specific penalty factors to penalize
different data sources differently. By combining integrative penalty factors
(IPF) with tree-guided group lasso, we create the IPF-tree-lasso method. We
present a unified framework to transform more general IPF-type methods to the
original penalized method. Because the structured penalty terms have multiple
parameters, we demonstrate how the interval-search Efficient Parameter
Selection via Global Optimization (EPSGO) algorithm can be used to optimize
multiple penalty parameters efficiently. Simulation studies show that
IPF-tree-lasso can improve the prediction performance compared to other
lasso-type methods, in particular for heterogenous data sources. Finally, we
employ the new methods to analyse data from the Genomics of Drug Sensitivity in
Cancer project.Comment: Zhao Z, Zucknick M (2020). Structured penalized regression for drug
sensitivity prediction. Journal of the Royal Statistical Society, Series C.
19 pages, 6 figures and 2 table
Machine Learning and Integrative Analysis of Biomedical Big Data.
Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues
Incorporating Pathway Information into Feature Selection Towards Better Performed Gene Signatures
To analyze gene expression data with sophisticated grouping structures and to extract hidden patterns from such data, feature selection is of critical importance. It is well known that genes do not function in isolation but rather work together within various metabolic, regulatory, and signaling pathways. If the biological knowledge contained within these pathways is taken into account, the resulting method is a pathway-based algorithm. Studies have demonstrated that a pathway-based method usually outperforms its gene-based counterpart in which no biological knowledge is considered. In this article, a pathway-based feature selection is firstly divided into three major categories, namely, pathway-level selection, bilevel selection, and pathway-guided gene selection. With bilevel selection methods being regarded as a special case of pathway-guided gene selection process, we discuss pathway-guided gene selection methods in detail and the importance of penalization in such methods. Last, we point out the potential utilizations of pathway-guided gene selection in one active research avenue, namely, to analyze longitudinal gene expression data. We believe this article provides valuable insights for computational biologists and biostatisticians so that they can make biology more computable
Computational translation of genomic responses from experimental model systems to humans
The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human "Translation Problems" defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches.Boehringer Ingelheim PharmaceuticalsInstitute for Collaborative Biotechnologies (Grant W911NF-09-0001
Bayesian hierarchical graph-structured model for pathway analysis using gene expression data
In genomic analysis, there is growing interest in network structures that represent biochemistry interactions. Graph structured or constrained inference takes advantage of a known relational structure among variables to introduce smoothness and reduce complexity in modeling, especially for high-dimensional genomic data. There has been a lot of interest in its application in model regularization and selection. However, prior knowledge on the graphical structure among the variables can be limited and partial. Empirical data may suggest variations and modifications to such a graph, which could lead to new and interesting biological findings. In this paper, we propose a Bayesian random graph-constrained model, rGrace, an extension from the Grace model, to combine a priori network information with empirical evidence, for applications such as pathway analysis. Using both simulations and real data examples, we show that the new method, while leading to improved predictive performance, can identify discrepancy between data and a prior known graph structure and suggest modifications and updates
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